Alkali metal fluorides are well-known agents for the conversion of ring-chlorinated pyridines to the corresponding fluoropyridines. Thus, Finger, et al. (J. Org. Chem. 28, 1666 1963)), found that KF in dimethyl sulfone at 200.degree. C. over a period of time converted 2-chloropyridine to 2-fluoropyridine. Similarly, 2,3,5-trichloro- and 2,3,5,6-tetrachloropyridine gave the 2-fluoro- and 2,6-difluoro-3,5-dichloropyridines.
It is equally well-known that the exchange of chlorine on pyridine for fluorine using the nucleophilic action of fluoride ion very strongly favors replacement at the alpha- or gamma-positions of chloropyridines, with a beta-chlorine remaining essentially inert. Thus, in addition to the above cases, it has been noted by Chambers, et al. (Proc. Chem. Soc. 1964, 83) that pentachloropyridine, for example, strongly favors exchange at the alpha- and gamma-positions when heated to ca. 200.degree. C. in a polar, aprotic diluent, and only under extreme conditions (anhydrous KF, 400.degree.-500.degree. C., 24 hr) does the exchange of the beta (3- and 5-) chlorines occur. Moreover, whenever this exchange at the beta (3 and/or 5) position has been observed, it has been limited to fully-substituted chloropyridines: the above-mentioned 2,3,5,6-tetrachloropyridine (having a hydrogen at the 4-position) gives only decomposition products under these conditions (Chambers, loc cit.). In closely-related substitution reactions, a beta-chloropyridine has been found to be 10,000-100,000 times less reactive than the alpha-chloro or gamma-chloropyridine, and theoretical explanations have been offered (Newkome and Paudler, "Contemporary Heterocyclic Chemistry", New York, John Wiley (1982), pp 262-3). European Patent Application No. 63,872 teaches that it is known to react chloropyridines with KF, in the presence or absence of a polar aprotic diluent, in order to replace chlorine by fluorine. However, EP No. 63,872 discloses on page 5 that when 2,3-dichloro-5-(trichloromethyl)pyridine is allowed to react with KF that the chlorine in the 3-position (beta-position) remains unchanged while all the other chlorine atoms are replaced by fluorine. The resulting product is 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine.
Similarly, the use of CsF as a fluorinating agent is taught in, e.g., European Patent Application Nos. 104,715 and 97,460 and in copending Application Ser. No. 564,800. These applications teach what are believed to be the first examples of direct substitution (with fluoride ion) of fluorine for the chlorine on a 3-chloropyridine having hydrogen on the ring. EP No. 97,460 cites the reaction of CsF with 3-chloro-2-cyano-5(trifluoromethyl)pyridine to yield the beta-fluoropyridine. ##STR1## In this example, the well-known influence of an adjacent cyano group on an aromatic ring, which powerfully activates a halogen (chlorine) toward substitution (by fluoride), is believed to be operating.
EP No. 104,715 discloses that fluoride ion from cesium fluoride in an aprotic diluent will react with 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine to give 2,3-difluoro-5-(trifluoromethyl)pyridine.